scholarly journals Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing’s Sarcoma

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1300
Author(s):  
Fatu Badiane Markey ◽  
Brigette Romero ◽  
Vijay Parashar ◽  
Mona Batish
Keyword(s):  
Transcription Factor ◽  
Single Molecule ◽  
Drug Targets ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Transmembrane Protein ◽  
Chromosomal Translocation ◽  
Therapeutic Interventions ◽  
Tumor Invasiveness ◽  
Novel Drug

Ewing’s sarcoma (ES) is caused by a chromosomal translocation leading to the formation of the fused EWSFLI1 gene, which codes for an aberrant transcription factor EWSFLI1. The transcriptional targets of EWSFLI1 have been viewed as promising and novel drug targets in the treatment of ES. One such target is six transmembrane epithelial antigen of the prostate 1 (STEAP1), a transmembrane protein that is upregulated by EWSFLI1 in ES. STEAP1 is a hallmark of tumor invasiveness and an indicator of tumor responsiveness to therapy. EWSFLI1 binds to the STEAP1 promoter region, but the mechanism of action by which it upregulates STEAP1 expression in ES is not entirely understood. Upon analysis of the STEAP1 promoter, we predicted two binding sites for NKX2.2, another crucial transcription factor involved in ES pathogenesis. We confirmed the interaction of NKX2.2 with the STEAP1 promoter using chromatin immunoprecipitation (ChIP) analysis. We used single-molecule RNA imaging, biochemical, and genetic studies to identify the novel role of NKX2.2 in regulating STEAP1 expression in ES. Our results show that NKX2.2 is a co-regulator of STEAP1 expression and functions by interacting with the STEAP1 promoter at sites proximal to the reported EWSFLI1 sites. The co-operative interaction of NKX2.2 with EWSFLI1 in regulating STEAP1 holds potential as a new target for therapeutic interventions for ES.

scholarly journals Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Ashley A. Kowalewski ◽  
R. Lor Randall ◽  
Stephen L. Lessnick
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Target Genes ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Cell Cycle Control ◽  
Chromosomal Translocation ◽  
Published Data ◽  
Pediatric Tumor ◽  
Cell Cycle Deregulation

Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered.

Molecular Biology of the Ewing’s Sarcoma/Primitive Neuroectodermal Tumor Family

2000 ◽  
Vol 18 (1) ◽  
pp. 204-204 ◽  
Author(s):  
Enrique de Alava ◽  
William L. Gerald
Keyword(s):  
Transcription Factor ◽  
Molecular Biology ◽  
Primitive Neuroectodermal Tumor ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Regulation Of Gene Expression ◽  
Tumor Biology ◽  
Chromosomal Translocation ◽  
Neuroectodermal Tumor ◽  
Prognostic Information

ABSTRACT: Ewing’s sarcoma (ES) and primitive neuroectodermal tumor (PNET) are members of a tumor family consistently associated with chromosomal translocation and functional fusion of the EWS gene to any of several structurally related transcription factor genes. Similar gene fusion events occur in other mesenchymal and hematopoietic tumors and are tumor-specific. The resulting novel transcription factor–like chimeric proteins are believed to contribute to tumor biology by aberrant regulation of gene expression altering critical controls of cell proliferation and differentiation. These tumor-specific molecular rearrangements are useful for primary diagnosis, may provide prognostic information, and present potential therapeutic targets. The recent advances in our understanding of the molecular biology of ES and PNET represent a paradigm for the application of the basic biology of neoplasia to clinical management of patients.

scholarly journals The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1.

1993 ◽  
Vol 13 (12) ◽  
pp. 7393-7398 ◽  
Author(s):  
W A May ◽  
S L Lessnick ◽  
B S Braun ◽  
M Klemsz ◽  
B C Lewis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Primitive Neuroectodermal Tumor ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Fusion Gene ◽  
Consensus Sequence ◽  
Transcriptional Activator ◽  
Neuroectodermal Tumor ◽  
Amino Terminal ◽  
Transforming Gene

EWS/FLI-1 is a chimeric protein formed by a tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. EWS/FLI-1 has been shown to be a potent transforming gene, suggesting that it plays an important role in the genesis of these human tumors. We now demonstrate that EWS/FLI-1 has the characteristics of an aberrant transcription factor. Subcellular fractionation experiments localized the EWS/FLI-1 protein to the nucleus of primitive neuroectodermal tumor cells. EWS/FLI-1 specifically bound in vitro an ets-2 consensus sequence similarly to normal FLI-1. When coupled to a GAL4 DNA-binding domain, the amino-terminal EWS/FLI-1 region was a much more potent transcriptional activator than the corresponding amino-terminal domain of FLI-1. Finally, EWS/FLI-1 efficiently transformed NIH 3T3 cells, but FLI-1 did not. These data suggest that EWS/FLI-1, functioning as a transcription factor, leads to a phenotype dramatically different from that of cells expressing FLI-1. EWS/FLI-1 could disrupt normal growth and differentiation either by more efficiently activating FLI-1 target genes or by inappropriately modulating genes normally not responsive to FLI-1.

scholarly journals Primary Ewing’s Sarcoma of the Sinonasal Tract: A Case Report

2017 ◽  
Vol 10 (1) ◽  
pp. 91-97 ◽  
Author(s):  
Tomoharu Suzuki ◽  
Ryuji Yasumatsu ◽  
Torahiko Nakashima ◽  
Shuji Arita ◽  
Hidetaka Yamamoto ◽  
...  
Keyword(s):  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Maxillary Antrum ◽  
Chromosomal Translocation ◽  
Microscopic Analysis ◽  
Complete Removal ◽  
Mri Scans ◽  
History Of ◽  
Mitotic Figures ◽  
Contiguous Spread

A 23-year-old male presented with a 3-month history of left purulent rhinorrhea, progressive nasal obstruction, and intermittent epistaxis. A fiberoptic examination revealed a large vascular polypoid mass completely filling the left nasal cavity. CT and MRI scans showed a large hypervascular mass involving the left nasal airway, maxillary antrum, and the anterior ethmoid cells. There was no bony erosion or contiguous spread, and the remaining sinuses, orbit, and cranial fossa were uninvolved. The patient underwent complete removal of the mass via an external lateral rhinotomy approach. The soft mass was large and vascular. A microscopic analysis revealed an undifferentiated tumor consisting of a solid sheet of small, round blue cells. Mitotic figures were also present. Immunohistochemically, the tumor cells were strongly positive for CD99. Molecular studies using a PCR confirmed the chromosomal translocation of FLI1 (exon 6). These findings were considered diagnostic for Ewing’s sarcoma. Postoperatively, the patient was treated with combined chemotherapy and radiotherapy. Adjuvant chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (total: 7 cycles) was commenced. He also received radiation therapy for local control (total dose: 50.4 Gy). The patient is currently alive without any evidence of recurrence or metastasis.

scholarly journals Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Olivia Simmons ◽  
Phillip B. Maples ◽  
Neil Senzer ◽  
John Nemunaitis
Keyword(s):  
Rna Interference ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Advanced Disease ◽  
Chromosomal Translocation ◽  
Transcription Factor Gene ◽  
Factor Gene ◽  
Systemic Rnai ◽  
Ets Transcription Factor ◽  
Target Sequences

Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. These unique target sequences provide opportunity for RNA interference(i)-based therapy. A summary of RNAi mechanism and therapeutically designed products including siRNA, shRNA and bi-shRNA are described. Comparison is made between each of these approaches. Systemic RNAi-based therapy, however, requires protected delivery to the Ewing's sarcoma tumor site for activity. Delivery systems which have been most effective in preclinical and clinical testing are reviewed, followed by preclinical assessment of various silencing strategies with demonstration of effectiveness to EWS/FLI-1 target sequences. It is concluded that RNAi-based therapeutics may have testable and achievable activity in management of Ewing's sarcoma.

scholarly journals Extraskeletal Ewing's sarcoma in a great toe of a young boy

2007 ◽  
Vol 15 (3) ◽  
pp. 165-168 ◽  
Author(s):  
Tatiana Karine Simon Cypel ◽  
Benjamin Meilik ◽  
Ronald Melvin Zuker
Keyword(s):  
Differential Diagnosis ◽  
Clinical Case ◽  
Ewing’S Sarcoma ◽  
Histological Analysis ◽  
Ewing's Sarcoma ◽  
Malignant Neoplasm ◽  
Chromosomal Translocation ◽  
Round Cell ◽  
Great Toe ◽  
Extraskeletal Ewing’S Sarcoma

Extraskeletal Ewing's sarcoma (EES) is a rare, soft tissue, malignant neoplasm histologically similar to skeletal Ewing's sarcoma. It occurs mainly in adolescents and young adults, and affects extremities in 36% of cases and central locations (commonly paravertebral regions) in the remainder. The differential diagnosis includes other small, blue, round cell tumours. A clinical case of EES involving a great toe in a young boy is reported. EES diagnosis was confirmed by features of histological analysis and immunohistochemistry, and by the presence of the t(11;22) chromosomal translocation.

scholarly journals Xg Expression in Ewing's Sarcoma Is of Prognostic Value and Contributes to Tumor Invasiveness

2010 ◽  
Vol 70 (9) ◽  
pp. 3730-3738 ◽  
Author(s):  
Ophélie Meynet ◽  
Katia Scotlandi ◽  
Emmanuelle Pradelli ◽  
Maria C. Manara ◽  
Mario P. Colombo ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Tumor Invasiveness
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